Bone metastases are the most common cause of cancer pain, and primary bone cancers may also cause severe chronic pain. Approximately 75-80% of patients with prostate, breast, and lung cancer develop osseous metastases which cause bone pain during the late stages of their illness. Clinical management of cancer-related bone pain through palliation is necessary to improve the quality of life of terminal cancer patients.
A number of options are currently available for clinical management of bone pain. Nonsteroidal anti-inflammatory agents, opioids, hormones, and cytotoxic chemotherapy are used in the initial stages of bone metastasis, and external beam radiation can be applied locally when bone pain occurs at a single site. As the patient""s skeletal tumor burden increases, pain can increase and become multifocal, tending to move from one site to another. Hemibody external beam radiation can afford rapid pain relief for disseminated skeletal tumors. However, such extensive exposure to radiation may affect noncancerous rapidly dividing tissues in the gastrointestinal tract or bone marrow, and morbidity may result from hemibody radiotherapy for bone pain palliation.
Radiation emitted by intravenously administered radionuclides may also be used to treat bone pain palliation. A number of bone-seeking radioisotopes have been studied for their ability to palliate bone pain. For example, 32P, which emits a 1.7 MeV xcex2 particle and has a half-life of 14.3 days, exhibits a 3- to 5-fold increase in uptake in bone around osseous metastases as compared to normal bone. The uptake of 32P into bone lesions can be increased by pretreatment with androgen, and patients thus treated frequently experienced pain relief within five to fourteen days of 32P orthophosphate administration, with response duration of two to four months. However, bone marrow receives a disproportionately high dose of 32P from the surrounding inorganic bone matrix and from the cellular component of the bone marrow space, resulting in myelosuppression as a side effect. Pancytopenia resulting from myelosuppression by 32P, though reversible, may necessitate transfusions. 32P orthophosphate is not currently used for palliation of metastatic bone pain.
153Sm emits an 0.81 MeV xcex2 particle, with a half-life of 46.3 hours. The stable 153Sm ethylenediaminetetramethylenephosphonate (EDTMP) complex has received FDA approval. Patients report clinical benefit within two weeks of 153Sm-EDTMP treatment, frequently within 48 hours of treatment, and pain relief may last from four to forty weeks. Reversible myelosuppression also results from bone pain palliation treatment with 153Sm-EDTMP. In addition, at the applied therapeutic doses (35 to 210 mCi) large amounts of radioactivity can be excreted in the patient""s urine, creating contamination risks and potentially causing radiation cystitis.
186Re emits a 1.07 MeV xcex2 particle and a 137 keV, 9% abundance xcex3 photon, having a half-life of 89.3 hours. 186Re forms a stable complex with hydroxyethylidine diphosphonate (HEDP) which rapidly accumulates in osteoblastic metastases. Symptom relief occurs for 40-65% of patients within two weeks, and frequently within 24-48 hours. 186Re-HEDP causes reversible myelosuppression, and therapeutic doses of 186Re-HEDP (30 to 70 mCi) also create contamination and radiation cystitis risks. Phase III clinical trials of 186Re-HEDP have been completed.
89Sr emits a 1.46 MeV xcex2 particle and has a half-life of 50.5 days. The biological half-life of 89Sr exceeds 50 days in osteoblastic metastases, as compared to 14 days in normal bone. Bone pain relief occurs in 60 to 80% of patients, with onset two to four weeks after injection, though some patients may not experience relief for as much as ten weeks after treatment. The average duration of relief from 89Sr treatment is from three to six months. Treatment with 89Sr delays development of new bone pain in pre-existing, but clinically silent metastases. Four weeks after therapy, 89Sr treatment typically causes a 30% decrease in platelet count, which recovers slowly over 12 weeks. Toxicity from 89Sr treatment is cumulative, resulting from the total absorbed dose of radiation delivered to the bone marrow and from replacement of marrow by tumor as disease advances. In 1993, the FDA approved an adult dosage of 4 mCi of 89SrCl2 for bone pain palliation.
Although pain relief is believed to occur independently from radiation-induced tumor cell killing, administration of bone pain-palliating doses of 153Sm and 186Re results in transient changes in levels of certain biochemical markers related to cancer progression. When administered with low doses of cisplatin, 89Sr also demonstrates reductions in tumor markers. This observation has led to the suggestion that administration of higher doses of these nuclides might result in a tumoricidal effect. However, no anti-tumor effect or improvement in survival has been demonstrated to result from administration of 153Sm, 186Re, or 89Sr, and the ability to increase dosages of these nuclides is limited by their myelosuppressive effects.
117mSn emits low energy conversion electrons (0.13 and 0.16 MeV) and a 159 keV photon, having a half-life of 14.0 days. 117mSn (Sn4+) diethylenetriaminepentaacetic acid (DTPA) exhibits higher bone uptake and retention than 32P orthophosphate, 153Sm-EDTMP, 186Re-HEDP, and 89SrCl2. Because of this, therapeutic doses of 117mSn (Sn4+) DTPA are lower than those of 153Sm-EDTMP and 186Re-HEDP, resulting in less risk of contamination and radiation cystitis. The lower energies of the conversion electrons emitted by 117mSn result in less radiation exposure to the bone marrow and fewer hematologic side effects than are observed with 153Sm-EDTMP, 186Re-HEDP, and 89SrCl2. The photon emitted by 117mSn allows imaging and quantification of the isotope in normal and metastatic bone. 117mSn(Sn4+) is particularly suitable for the dose escalation necessary to effect cell killing in osseous tumors, since the myelosuppression which limits the benefits of the anti-tumor effects of 153Sm, 186Re, and 89Sr is not a limiting factor for 117mSn(Sn4+).
Atkins, et al., Radiology (1993) 186, 279-283, discloses biodistribution of low doses of 117mSn (Sn4+) DTPA administered to humans. Atkins, et al. (1995) J. Nucl. Med. 36, 725-729 reports a Phase II pilot study which demonstrates palliation of bone pain resulting from 117mSn (Sn4+) DTPA treatment. A Phase II study of 117mSn (Sn4+) DTPA as a bone pain palliation agent is reported in Krishnamurthy, et al. (1997) J Nucl. Med. 38, 230-237. A dose escalation study of 47 patients treated with 117mSn (Sn4+) DTPA for bone pain palliation is reported in Srivastava, et al. (1998) Clin. Cancer Res. 4, 61-68. All of the 117mSn (Sn4+) DTPA formulations used in these studies contained a 20-fold molar excess of DTPA over 117mSn (Sn4+) and an amount of CaCl2 corresponding to 80% of the molar amount of DTPA. The CaCl2 was administered with the 117msn (Sn4+) DTPA to counteract any potential effect of uncomplexed DTPA on bone or blood calcium levels.
U.S. Pat. No. 4,533,541 discloses preparation of 117mSn (Sn4+) chelates capable of localizing to bone after intravenous injection, which were used for diagnostic purposes. The chelating agents disclosed in U.S. Pat. No. 4,553,541 include DTPA, which was formulated in significant molar excess (8-40-fold) over the concentration of 117mSn (Sn4+) (i.e., the concentration of total tin) in the radiopharmaceutical composition.
WO 95/29706 discloses 117mSn (Sn4+) DTPA compositions for bone pain palliation and bone cancer therapy, which employ a molar excess of DTPA over 117mSn (Sn4+). WO 95/29706 demonstrates dose-dependent relief of bone pain in humans after administration of 117mSn (Sn4+) DTPA, with particular efficacy at doses of about 9 to about 25 mCi per 70 kg body weight. None of the 117mSn (Sn4+) DTPA compositions used in WO 95/29706 exhibited bone marrow toxicity, thus providing a significant advantage over the known agents. In a preferred embodiment, CaCl2 was included with the 117mSn (Sn4+) DTPA compositions of WO 95/29706, to inhibit or retard possible hypocalcemic effects of the unchelated tin chelating agent DTPA.
U.S. Pat. No. 6,004,532 discloses a process for the manufacture of 117mSn(Sn4+)DTPA which includes the reaction of DTPA at a molar concentration from about eight to about twenty times the molar concentration of 117mSn(Sn4+) to form a 117mSn(Sn4+)DTPA complex and then removing the excess DTPA by chromatographic means. Because of the toxicity of the DTPA, this process requires the additional step of the removal of the excess DTPA.
The present invention provides a method of making a pharmaceutical composition of 117mSn(Sn4+)DTPA. This first method provided utilizes an aqueous solvent and is therefore termed xe2x80x9caqueous reactionxe2x80x9d herein. The method includes the steps:
a) dissolving metallic 117mSn in a concentrated acid suspended in an aqueous medium to form a 117mSnCl2 solution;
b) adding the DTPA to 117mSnCl2 solution in a molar concentration ratio of between about 1.0 to about 3.0 DTPA to 117mSnCl2;
c) allowing the 117mSnCl2 to react with the DTPA to form a 117mSn(Sn2+)DTPA complex;
d) oxidizing the 117mSn(Sn2+)DTPA to form a composition comprising 117mSn(Sn4+)DTPA; and
e) removing the concentrated acid and water from the solution to form to form a resulting solid composition comprising 117mSn(Sn4+)DTPA complex with a molar ratio of DTPA to 117mSn(Sn4+) of about 1.0 to about 3.0. In a preferred embodiment, the resulting composition comprises 117mSn(Sn4+)DTPA with a molar ratio of DPTA to 117mSn(Sn4+) of about 1 to about 1.2.
In a separate embodiment, another method of making a pharmaceutical composition of 117mSn(Sn4+) DTPA is provided. This method utilizes organic solvents and therefore is termed the xe2x80x9corganic reactionxe2x80x9d herein. This method the steps:
a) dissolving metallic 117Sn in a concentrated acid suspended in an aqueous medium to form a 117mSnCl2 solution under an inert atmosphere;
b) adding DTPA to the 117mSnCl2 solution in a molar concentration ratio of between about 1.0 to about 3.0 DTPA to 117mSnCl2 in an inert atmosphere;
c) removing the concentrated acid and water from the solution to form a solid residue comprising unchelated 117mSnCl2 and DTPA;
d) dissolving the solid residue in an organic solvent to form an organic mixture,
e) allowing the organic mixture to react sufficient to allow the formation of a 117mSn(Sn2+)DTPA complex;
f) oxidizing the 117mSn(Sn2+)DTPA to form a resulting composition comprising 117mSn(Sn4+)DTPA with a molar ratio of DTPA to 117mSn(Sn4+) of about 1.0 to about 3.0.
In a preferred embodiment, the resulting composition comprises 117mSn(Sn4+)DTPA with a molar ratio of DPTA to 117mSn(Sn4+) of about 1 to about 1.2.
The pharmaceutical composition manufactured by each of the aqueous reaction and organic reaction is also provided. These pharmaceuticals can be utilized in a method of treating primary or metastatic tumor in skeletal bone of a mammal. The method includes administering to the mammal a therapeutically effective amount of the pharmaceutical manufactured by either the aqueous or organic reactions.
A method of treating bone pain is also provided herein. This method also includes administering to a mammal a bone palliating amount of a pharmaceutical manufactured by either the aqueous or organic reaction method.
The method of the invention provides the benefit of a one-step reaction which, due to the ease of formulation, will result in minimizing personnel exposure, reduce waste, provide greater contamination control, and greatly simplify the eventual commercial production of 117mSn(Sn4+)DTPA. Unlike previous methods, the purification step to remove excess DTPA is not necessary in the method of the invention because DTPA and 117mSn(Sn4+) are reacted at an approximately 1:1 ratio. The 117mSn(Sn4+) DTPA produced by the method of the invention possesses the same chemical (shelf life and stability) and biological (biodistribution in mice) properties, compared to the current 20:1 117mSn(Sn4+)DTPA formulation.
Because the method of the invention can provide a composition having a lower ratio of DTPA to 117mSn(Sn4+) (i.e. less than 3:1), the composition resulting from the method of the invention contains less of the toxic unchelated DTPA. This reduced toxicity allows more of the composition to be administered which, in turn, also permits the use of low specific activity 117mSn. Therefore, the radiopharmaceutical produced by the method of the invention can be utilized in the higher quantities to not only provide pain palliation in bone cancer patients, but also be used for bone cancer treatment.